EDITOR’S NOTE: Dr. Irving Weissman has been the director of the Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, since 2003. He is also a brother of our own Jerry Weissman. Besides being extremely interesting, I found this article to be encouraging for those of us who may not do well in a traditional school setting, but who nevertheless have a child’s insatiable curiosity to find out how things work. I’m sure Dr. Weissman didn’t have a clue that his curiosity would lead him to be so influential and successful in the emerging field of stem cell research. It is also interesting to contemplate what are the attributes of a good leader, and what sustains an environment of learning at an institute and what could kill it.

Stepping down but not leaving

I’m writing this explanation for the faculty and staff of the Institute for Stem Cell Biology and Medicine, and for all of the trainees, and especially for the individual donors and other institutions and foundations that allowed the birth and growth of the institute. And I hope it is also useful for the Stanford search committee that will choose my successor, and our Scientific Advisory Board who are all leading stem cell biologists, and whose advice should help the committee make the right choice.

When I was 10 and growing up in Great Falls, Montana, one of my teachers gave me a book called “Microbe Hunters” by Paul de Kruif. It was a book about the lives and work of the great microbe hunters of the past two centuries—people who may or may not have been trained scientists but who had in them the curiosity to wonder how things worked, people who discovered microbes and the diseases they caused—and who translated their discoveries as soon as they could to benefit the health of those stricken with these diseases. And when they got into these clues to “how things work,” they put all of their time and energy in their labs into their projects. Elsewhere, I’ve written about the incredible luck I’ve had to find, starting at 16 in high school, labs that were led by great role models such as Ernst Eichwald in Great Falls, a pathologist and immunogeneticist of tissue transplantation who worked in a rural hospital without a university or medical school. Eichwald had neither the time nor the inclination to tell me what to do and how, but left me largely on my own to explore the emerging fields of immunology and transplantation and cancer, and how my own brand of ‘how things work’ emerged to ask how the systems developed from fetal life on.

I had curiosity, I had the openings to work in a lab (actually, none of us think of it as work), but I didn’t know if I had the drive to go at it day and night, weekdays and weekends, like the microbe hunters, or have their ability to translate discoveries.

I knew I didn’t have the discipline to devote hours to memorizing texts to get great grades—in all of my schooling I never made the honor roll (the top 10% in grades). But when I hit my subject, I realized it took no discipline to be completely absorbed, to observe and to ask how did things work and how did systems develop to get what I observed and could verify by experiment. In fact, I did not have the discipline not to spend as much time as I could in the research. Albeit, much of the time I’d be doing all the other things my Montana friends and I did during high school and college, but my mind was always on the research questions that came from my observations and experiments. In retrospect, perhaps the greatest part of my luck was that the three patrons/mentors in my career¬–Ernst Eichwald in Montana, Henry Kaplan at Stanford, and Jim Gowans at Oxford–never told me what research to do. So I got to follow my own curiosity from high school on, learning more from what these mentors had accomplished than I could by having them manage (or micromanage) my research. Eichwald taught me that genetics can show what can happen, Gowans taught me that physiological experiments in the body can show what does happen, and Henry Kaplan, the great radiologist who founded the radiation treatments of cancers, taught me that basic science can be translated to curative human therapies. From that, I finally came to understand that all humans with diseases were in fact experiments of nature, and that they had in their bodies the hidden life-history of how the diseases developed—in my view often from stem cells—and which, if understood, could lead to therapies.

As I said already, I’ve told the story of my luck and life in science elsewhere many times. But now that I’m stepping down from the directorship of the institute, and from a position of leadership in a field that I was lucky enough to discover and develop, I wonder if, and whether, and how this legacy might continue at Stanford.

What is the field? Officially it’s stem cells, which are the only cells in the born organism that sustains all of the tissues and organs for life, and which can reveal the secrets of almost all–if not all–diseases that occur after we are born, as well as the therapies (including by transferred healthy stem cells) that can continue healthy regeneration. In born organisms, blood stem cells make blood and only blood, brain stem cells make brain and only brain, and so on.

What is the defining characteristic of stem cells? Only stem cells in these tissues and organs make more of themselves when they divide, which is now called self-renewal. Except for renewed stem cells, all of the daughter cells from cell divisions go through decision trees to change states quantally, so that a blood-forming stem cell self-renews blood-forming stem cells They do this by keeping open for expression the genes that were open in the parent stem cell, and keeping closed those that would take it out of self-renewal. But some of the daughter cells of stem cells open some genes that were closed, and closes others that were open, to make a daughter progenitor cell that can make all blood cells (multipotent progenitor or MPP) but cannot self-renew.

Other quantal steps give rise to progenitor cells with more restricted potential, some of which will make red blood cells and platelets, while others make the innate immune system’s macrophages and neutrophiles that scavenge microbes or dying or dead–or as we found–dangerous cells or organisms. Yet other progenitors make the lymphocytes that, at the single cell level, are each precommitted to recognize the foreign shape of microbes or chemicals or cancer cells or tissue transplants from a donor. The rare lymphocyte that encounters those shapes divide like stem cells in self-renewal to make thousands of immune cells with the same or almost the same immune receptors for shapes as the cell they came from. This activity is the basis of vaccinations and our natural immunity that protect us from microbes previously encountered, even in childhood.

I started in the field of lymphocytes, drawn by the amazing properties of immune lymphocytes. I studied only one population of lymphocytes initially—the T cells born in the thymus (I showed that while a medical student in Jim Gowans’ lab in Oxford) that mediate rejection of cells, not microbes, but cells infected by microbes. Other lymphocytes called B cells looked just like T cells, but when their cell surface immune receptors were discovered, they were the precursors of antibodies that permeate all intercellular spaces in the body, and which bring in other proteins or cells to destroy the microbes for which their antibody combining sites were selected. While many, including Gowans, thought that T and B cells were just minor variations from each other, several labs had discovered in birds that T cells came from the thymus, and B cells from an organ called the Bursa. I decided to track the origins of both T cells and B cells, and that led me to blood forming stem cells.

From there came the clinical transplantation of human blood stem cells, and then isolation of human fetal brain stem cells and their translation, then the role of normal stem cells in the stepwise generation of cancer stem cells, with the understanding of blood forming stem cell clones as the requisite cell types that can accumulate a few dangerous mutations and a lot of irrelevant mutations. The understanding that one could use purified normal and leukemia (or other cancer) stem cells to understand which changes occur at each step of the transition from normal stem cells to cancer stem cells has revealed a strange and unexpected fact: a mutation or chromosomal anomaly in a single (blood-forming) stem cell can allow that cell to migrate to compete for other stem cell homes (niches), and eventually most or all blood formation comes from that altered stem cell, creating a widespread group of diseases that previously were not understood. And the leukemia stem cells overexpressed a surface protein that prevented scavenger macrophages from eating them, even though some of the mutations had led the cell to put out an ‘eat me’ danger signal that mediated the macrophages to eat and kill them. We now know that all cancers and at least some pre-cancers, and all atherosclerotic lesions causing heart attacks and strokes, and all tested fibrotic diseases of the lung, liver, kidney, skin, etc follow this model. We also know that therapeutics for blocking “don’t eat me” signals such as CD47 in cancers have high potential to treat these very common, but often incurable, other diseases.

Why have I explained this background in detail? This is a story, not the only story, of how a field can be opened and expanded and exploited for medical translation. It had no relevance to how most people get into their career—straight A’s, elite schools, privileged advancement, etc. It didn’t really fit the model of a boss directing employees daily on what to do and how—essentially treating trainees as imperfect ‘helpers’ whose own judgements needed daily oversight and correction. Giving them the chance to solve problems led many of them to have confidence needed for their own careers when they left the lab. These were hard lessons to learn. I learned those lessons early, and using that as a guide, have been lucky enough to attract extremely talented ‘B’ students, many of whom have developed fields and achieved leadership on their own, now mainly in stem cell fields. I learned to step back and be more ‘Socratic’ in my oversight of trainees rather than being directive. Often, I was surprised at weekly lab meetings with an incipient discovery by a trainee at any level that I realized could open an understanding, or even a field. Discoveries, not slavish adherence to my direction, was the result.

Our institute is mainly, if not exclusively, populated by creative, innovative, original, self-directed, and highly successful biomedical scientists and physician-scientists. The discoveries coming from them should provide the rationale behind stem cell discovery science and stem cell related translations long into the future. You would think, therefore, that the institute is safe. But it isn’t. I’ve seen over and over great immunology groups at other universities or institutes be decimated overnight. Immunology, although a discipline as powerful and important as genetics or biochemistry, has not been either a department or safe organizational unit in universities, while genetics and biochemistry, for example are departments with over a century lifespan in the US at all universities. That is not true for immunology. New department heads (or deans) in schools with high level immunology groups have ended those programs as they change the departments’ directions. Hopefully, that won’t be true for stem cell biology and regenerative medicine.
We were established by Dean Philip Pizzo, who recognized that the inward focus of departments, with allegiance to their discipline, ran counter to the multidisciplinary nature of the emerging biomedical sciences. To break out of that inward focus, he established several institutes at Stanford. There was no history of stem cell science before the late 20th century. Very few of us were establishing that field. Ours was one of the first institutes at the Stanford School of Medicine. All appointments in institutes were initiated by institutes, and departments were added to search committees to make sure that was happening in institutes could inform and be enriched by departments. Institutes could cross the basic science/clinical medicine barrier, and so it could be natural to make discoveries, and to try to translate them for the benefit of patients. (It is another story how biotech and large pharmaceutical companies were not and are not the best early vehicles to cross the discovery to therapy ‘valley of death.’)

Luckily, at least for the present, the establishment and re-establishment of the California Institute of Regenerative Medicine, CIRM, as an important state agency that supports all aspects of California programs/centers/departments/institutes of stem cell biology and regenerative medicine, funding eager future scientists in high school, college, post-college bridges, graduate and medical students, postdoctoral trainees, and faculties and institutions, as well as providing in academia incubation of translation of discoveries. But that too is impermanent and can change rapidly.

For the backers of the institute and the committee to choose the next director, it is critical that the next director be a stem cell discovery scientist. There are many who claim to be stem cell scientists, but most of the claims are just not true. That is why we have a Scientific Advisory Board made up of eight major stem cell discovery scientists to advise the director, the dean, and hopefully the search committee. The search will hopefully investigate whether potential candidates have trained next generation leaders of the field, or if the candidates have already been a chair or director, if the faculty he/she served had successful stem cell discovery and/or translation careers. Another critical trait will be the ability to explain their science in plain English to non-scientists, which will enable future donors or legislators or students to understand what the institute does, and how it might be able to achieve the translation of stem cell science.

I do want to end by saying that “I ain’t done yet.” There are areas of stem cell science and the evolution of stem cells that wake me up at night, and consume my thoughts even when fly-fishing. I hope to keep on this track until I can’t contribute to the field anymore. It has been an honor to help establish this field here, and for that I am grateful to all of you.
Irv Weissman
2021